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Figure 1. MCL DIAGNOSIS AND WORK-UP PATHWAY1

DIAGNOSIS
  • Excisional or incisional biopsy

    –  FNA biopsy alone is generally not suitable for the initial diagnosis of lymphoma

    –  Core needle biopsy is not optimal but can be used under circumstances

    –  In certain circumstances, when a lymph node is not easily accessible for excisional or incisional biopsy, a combination of core biopsy (multiple biopsies preferred) and FNA biopsies in conjunction with appropriate ancillary techniques for the differential diagnosis (IHC, flow cytometry, PCR for IGHV and TCR gene arrangements, karyotype, and FISH for major translocations*) may be suitable

  • Histologic grading cannot be performed on an FNA
  • Hematopathology review of all slides with ≥1 paraffin block representative of the tumour; rebiopsy if consult material is non‑diagnostic

ADDITIONAL DIAGNOSTIC TESTING

  • Essential
    • Adequate immunophenotyping to establish diagnosisa

        –  IHC panel: CD20, CD3, CD5, cyclin D1, CD10, CD21, CD23, BCL2, BCL6, TP53, SOX11, Ki-67 b with or without

        –  Cell surface marker analysis by flow cytometry with peripheral blood and/or biopsy specimen: kappa/lambda, CD19, CD20, CD5, CD23, CD10, CD200

        –  TP53 sequencingcc

    Useful in certain circumstances
    • IHC: LEF1 may help distinguish from variant CLL; SOX11 or IGHV sequencing may be useful for determination of clinically indolentd MCL; may also help in diagnosis of CCND1- MCL
    • Karyotype or FISH: t(11;14), t(14;18), CLL panel
    • Cell surface marker analysis by flow cytometry with peripheral blood and/or biopsy specimen: CD200

WORK-UP

  • Essential
    • Physical exam: attention to node-bearing areas, including Waldeyer’s ring, and to size of liver and spleen
    • Performance status
    • B symptoms
    • CBC with differential
    • Comprehensive metabolic panel
    • LDH
    • C/A/P CT with contrast of diagnostic quality
    • Whole-body PET/CT scan essential if RT for Stage I, II disease or systemic therapy is planned
    • Hepatitis B testinge if rituximab contemplated
    • Echocardiogram or MUGA scan if anthracycline or anthracenedione-based regimen is indicated
    • Pregnancy testing in women of child-bearing age (if chemotherapy or RT planned)
    Useful in certain circumstances
    • Endoscopy/colonoscopyf
    • Bone marrow biopsy ± aspirate
    • Neck CT with contrast
    • Uric acid
    • beta-2 microglobulin
    • Hepatitis C testing
    • Lumbar puncture (for blastic variant or CNS symptoms)
    • Discussion of fertility issues and sperm banking

FNA=fine needle aspiration; IHC=immunohistochemistry; PCR=polymerase chain reaction; IGHV=immunoglobin heavy chain variable; TCR=T-cell receptor; FISH=fluorescent in situ hybridization; LEF1=lymphoid enhancer-binding factor 1; CLL=chronic lymphocytic leukemia; CCND1=cyclin D1; CBC=complete blood count; LDH=lactate dehydrogenase; C/A/P=chest/abdominal/pelvic; CT=computerized tomography; PET=positron emission tomography; RT=radiotherapy; MUGA=multigated acquisition; CNS=central nervous system.

*    If a high suspicion of a clonal process remains and other techniques have not resulted in a clear identification of a clonal process, then next-generation sequencing (NGS) can be used.

  1. Typical immunophenotype: CD5+, CD20+, CD43+, CD23-/+, cyclin D1+, CD10-/+. Note: Some cases of MCL may be CD5- or CD23+. If the diagnosis is suspected, cyclin D1 staining or FISH for t(11;14) should be done. There are rare cases of CCND1- MCL (<5%) with an otherwise typical immunophenotype.
  2. Ki-67 proliferation fraction of <30% in lymph nodes is associated with a more favourable prognosis.
  3. TP53 mutation has been associated with poor prognosis in patients treated with conventional therapy, including transplant. Clinical trial is strongly suggested for these patients. TP53 by IHC is not a proven surrogate for TP53 mutation status or del(17p) status.
  4. Most common biomarker for indolent disease: SOX11- [IGHV-mutated]. Typical clinical presentation: leukemic non-nodal CLL-like with splenomegaly, low tumour burden, Ki-67 proliferation fraction <10%.
  5. Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and core antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen. If positive, check viral load and consider consult with gastroenterologist.
  6. Essential for confirmation of Stage I–II disease.

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.1.2022 – March 2, 2022. © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

TYPES OF MCL

Conventional MCL (70−80%)2

Symptomatic lymph adenopathy or symptomatic extra-nodal disease requiring systemic therapy.

Smouldering nodal/extra-nodal MCL and asymptomatic purely leukemic non-blastoid MCL (10−20%)2

A “watch and wait” strategy should be considered for patients with asymptomatic, low MIPI or elderly patients due to the unfavourable prognosis and the limited efficacy with standard therapy (i.e., does not appear to cure) in patients with MCL.2,3

symptoms of mcl

THE MCL DIAGNOSTIC PROCESS

LYMPH NODE BIOPSY

A diagnosis of MCL requires histopathological confirmation of lymph node infiltration. A part, or all, of an easily accessible, enlarged lymph node will be removed.4–6

The histological report should give the diagnosis according to the World Health Organization (WHO) classification and Ki-67, a proliferation marker, as the most established histomorphological risk factor.6

Most tumours have a classic structure of small−medium-sized cells with irregular nuclei. However, the malignant lymphocytes may present in a variety of forms.6

Immunophenotypic evaluation

Immunophenotyping using flow cytometry has become an integral part in the subclassification of B-cell lymphomas (Figure 2).7

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FIGURE 2. MCL IMMUNOPHENOTYPING2,3,7,8

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BCL2=B-cell lymphoma 2.

CLINICAL PRESENTATION

The MCL subtypes present with different clinical pictures.2

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TABLE 1. CLINICAL FEATURES OF MCL SUBTYPES2

MCL subtype Clinical features
Conventional MCL
  • Symptomatic bulky nodal/extra-nodal disease
  • Classic or blastoid/pleomorphic cytomorphology
  • Signs of clinical progression
Smouldering nodal/extra-nodal MCL
  • Lack of B symptoms (drenching night sweats, unintentional weight loss in ≤6 months of >10% of normal body weight, fever >38°C)
  • Normal serum LDH, beta-2 microglobin levels
  • WBC <3.0 x 109/L
  • Low MIPI score
  • Ki-67 on lymphoma cells in non-marrow tissue biopsy of <30%
  • Non-blastoid/pleomorphic cytomorphologic pattern in tissue biopsy
  • Max lymph node diameter <3 cm, spleen size <20 cm
  • PET scan showing the maximum SUV <6
  • DNA sequencing lacks TP53 or NOTCH1/2 mutations
  • FISH testing shows no deletion 17p or MYC translocation and an absence of complex karyotype
Asymptomatic purely leukaemic non-blastoid MCL
  • Monoclonal B lymphocytosis (with MCL immunophenotype and non-blastoid morphology) in peripheral blood or in bone marrow with/without splenomegaly

Adapted from Jain P and Wang M, 2019.
LDH=lactate dehydrogenase; WBC=white blood cell count; MIPI=mantle cell lymphoma international prognostic index; PET=positron emission tomography; SUV=standardized uptake value; FISH=fluorescent in situ hybridization.